Over-coated product including tableted center and medicament

ABSTRACT

Methods and products for delivering a medicament or agent to an individual are provided as well as methods for producing the product. The product includes a coating having a medicament or agent. The medicament or agent is present within the coating that surrounds a tableted center. The tableted center is defined by compressible excipients. By chewing the product, the medicament or agent is released from the product within the buccal cavity.

This is a divisional of U.S. patent application Ser. No. 09/631,326entitled “OVER-COATED CHEWING GUM FORMULATIONS INCLUDING TABLETEDCENTER” which is a continuation-in-part of U.S. patent application Ser.No. 09/618,808 filed on Jul. 18, 2000, which is a continuation-in-partof U.S. patent application Ser. No. 09/510,878, filed on Feb. 23, 2000,which is a continuation-in-part of U.S. patent application Ser. No.09/286,818, filed on Apr. 6, 1999 and PCT Patent Application No.PCT/US99/29742 filed on Dec. 14, 1999.

BACKGROUND OF THE INVENTION

The present invention generally relates to the delivery of medicamentsand other agents. More specifically, the present invention relates tothe delivery of medicaments and agents using chewing gum formulationsand methods for producing such products.

It is of course known to provide agents to individuals for variouspurposes. These agents can be used to treat diseases and as such aretypically referred to as drugs or medicaments. Likewise, the drugs ormedicaments can be used for prophylactic purposes. Still, it is known toprovide agents to an individual for a variety of non-medical purposesincluding enhancing performance or maintaining or initiating alertness.There are a great variety of such agents. These agents run the gamutfrom stimulants such as caffeine to drugs such as analgesics,tranquilizers, cardiovascular products, insulin, etc. Some such agentsare taken on an as needed basis while other agents must be taken atregular intervals by the individual.

Typically, drugs (medicaments) are administered parenterally orenterally. Of course, parenteral administration is the administration ofthe drug intravenously directly into the blood stream. Enteral refers tothe administration of the drug into the gastrointestinal tract. Ineither case, the goal of the drug administration is to move the drugfrom the site of administration towards the systemic circulation.

Except when given intravenously, a drug must traverse severalsemipermeable cell membranes before reaching general circulation. Thesemembranes act as a biological barrier that inhibits the passage of drugmolecules. There are believed to be four processes by which drugs moveacross a biological barrier: passive diffusion; facilitated diffusion;active transport; and pinocytosis.

Passive diffusion is the transport across the cell membrane wherein thedriving force for the movement is the concentration gradient of thesolute. In orally administered drugs, this absorption occurs in thesmall intestines. Facilitated diffusion is believed to be based on acarrier component that combines reversibly with the substrate moleculeat the cell membrane exterior. The carrier substrate complex diffusesrapidly across the membrane with release of the substrate at theinterior surface. Active transport requires an energy expenditure by thecell and appears to be limited to agents with structural similarities tonormal body constituents. These agents are usually absorbed fromspecific sites in the small intestines. Pinocytosis refers to theengulfing of particulars or fluid by a cell. It is believed to play aminor role in drug transport. Merck Manual, 16th Edition, pp. 2598-2599.

In determining the efficacy of a drug and the effectiveness of the useof a drug to treat a disease, drug absorption is a critical concern.Drug absorption refers to the process of drug movement from the site ofadministration toward the systemic circulation.

Oral administration of drugs is by far the most common method. Whenadministered orally, drug absorption usually occurs due to the transportof cells across the membranes of the epithelial cells within thegastrointestinal tract. Absorption after oral administration isconfounded by numerous factors. These factors include differences downthe alimentary canal in: the luminal pH; surface area per luminalvolume; perfusion of tissue, bile, and mucus flow; and the epithelialmembranes. See Merck Manual at page 2599.

A further issue effecting the absorption of orally administered drugs isthe form of the drug. Most orally administered drugs are in the form oftablets or capsules. This is primarily for convenience, economy,stability, and patient acceptance. Accordingly, these capsules ortablets must be disintegrated or dissolved before absorption can occur.There are a variety of factors capable of varying or retardingdisintegration of solid dosage forms. Further, there are a variety offactors that effect the dissolution rate and therefore determine theavailability of the drug for absorption. See Merck Manual at page 2600.

Parenteral administration allows for the direct placement of the druginto the blood stream. This usually insures complete delivery of thedose to the general circulation. However, administration by a route thatrequires drug transfer through one or more biologic membranes to reachthe blood stream precludes a guarantee that all of the drug willeventually be absorbed. Even with parenteral administration, becausecapillaries tend to be highly porous, the perfusion (blood flow/gram oftissue) is a major factor in the rate of absorption. Thus, the injectionsite can markedly influence a drugs' absorption rate; e.g., theabsorption rate of diazepam injected IM into a site with poor blood flowcan be much slower than following an oral dose. See Merck Manual at page2601.

Not only is drug absorption an issue in drug delivery but also thebioavailability of the drug is also critical. Bioavailability is definedas the rate at which and the extent to which the active moiety (drug ormetabolite) enters the general circulation, thereby gaining access tothe site of action. Bioavailability depends upon a number of factors,including how a drug product is designed and manufactured, itsphysicochemical properties, and factors that relate to the physiologyand pathology of the patient. See Merck Manual at page 2602.

When a drug rapidly dissolves from a drug product and readily passesacross membranes, absorption from most site administration tends to becomplete. This is not always the case for drugs given orally. Beforereaching the vena cava, the drug must move down the alimentary canal andpass through the gut wall and liver, which are common sites of drugmetabolism. Thus, the drug may be metabolized before it can be measuredin the general circulation. This cause of a decrease in drug input iscalled the first pass effect. A large number of drugs show lowbioavailability owing to an extensive first pass metabolism. The twoother most frequent causes of low bioavailability are insufficient timein the GI tract and the presence of competing reactions. See MerckManual at page 2602.

Bioavailability considerations are most often encountered for orallyadministered drugs. Differences in bioavailability can have profoundclinical significance.

Although parenteral administration does provide a method for eliminatinga number of the variables that are present with oral administration,parenteral administration is not a preferable route. Typically,parenteral administration requires the use of medical personnel and isjust not warranted nor practical for the administration of most agentsand drugs, e.g., analgesics. Even when required, parenteraladministration is not preferred due to patient concerns includingcomfort, infection, etc., as well as the equipment and costs involved.However, despite best efforts certain therapies require parenterallyinjected drugs. For example, research for decades has focused on anattempt to deliver insulin to an individual through a non-parenteralmeans. Despite such efforts, today insulin is still only administeredintravenously.

In producing products for delivering medicaments and other agents to anindividual, it may be critical that a predefined amount of medicament oragent is delivered per dose of the product. This allows the physicianand/or patient to determine the amount of product to ingest and insurethat a safe and effective level of medicament or agent is delivered. Ifthe medicament or agent is located in a coating of the product it isnecessary to ensure that definite levels of coating are present in eachproduct. This requires a manufacturing process that allows for theaccurate production of coated products.

A still further issue vis-à-vis drug delivery, and most specificallyoral drug delivery, is taste. Many over the counter and pharmaceuticalproducts are not available in a chewable form due to taste problems.Such products include, for example, excedrin, pseudoephedrin, and MaHuang/guarana diet pills.

Thus, there is a need for an improved method of delivering drugs andagents to an individual.

SUMMARY OF THE INVENTION

The present invention provides improved methods for manufacturingproducts for delivering a medicament or agent to an individual as wellas such products. To this end, a compressible excipient is tableted andthen coated to produce a coated product including a medicament or agent.The medicament or agent is present within the coating or shell thatsubstantially encloses the tableted compressible excipient. It has beenfound that by tableting the compressible excipient that a specificallydefined coating can be provided, providing a predetermined andcontrollable level of medicament or agent.

The excipient can be, by way of example and not limitation, dextrose,sucrose, or other saccharides, sorbitol, mannitol, iso-malitol, othercompressible sugar alcohols, or combinations thereof.

Improved formulations including medicaments or agents are also providedby the present invention.

To this end, the present invention provides a product including atableted compressible excipient. The tableted compressible excipient issubstantially surrounded by a coating. The coating includes a medicamentor agent and comprises at least 50% by weight of the product.

In an embodiment, the coating includes a masking agent to assist inimproving the organoleptic properties of the coating containing themedicament. The masking agent may be chosen from the group consistingof: sucralose; zinc gluconate; ethyl maltol; glycine; acesulfame-K;aspartame; saccharin; fructose; xylitol; spray dried licorice root;glycerrhizine; dextrose; sodium gluconate; glucono delta-lactone; ethylvanillin; vanillin; normal and high-potency sweeteners; and a variety ofappropriate flavors.

In an embodiment, the coating includes a high-intensity sweetener. In afurther embodiment, the high-intensity sweetener is chosen from thegroup consisting of aspartame, sucralose, and acesulfame-K.

In an embodiment, the compressible excipient is chosen from the groupconsisting of dextrose, sucrose, sorbitol, manitol, and combinations ofsame.

In an embodiment, the coating comprises 50% to 75% by weight of theproduct.

In an embodiment, the coating is a recrystallized granular coating.

In an embodiment, the coating is an amorphous coating.

In an embodiment, the coating is a powder coating.

In an embodiment, the medicament is chosen from the group consisting of:analgesics; muscle relaxants; antacids; antihistamines; decongestants;anti-inflammatories; antibiotics; antivirals; psychotherapeutic agents;insulin; nutraceuticals; nutritional supplements; and cardiovascularagents.

In another embodiment of the present invention a method of drug deliveryis provided. The method comprising the steps of: providing a productthat includes a compressible excipient that is substantially surroundedby a coating, the coating includes a medicament; chewing the product tocause the medicament to be released from the product into the buccalcavity of the chewer; and continuing to chew the product therebycreating a fluid pressure causing the medicament to enter the systemicsystem of the chewer through the oral mucosa contained in the buccalcavity.

In an embodiment of the method, the agent is a medicament. In anembodiment of the method, the medicament is chosen from the groupconsisting of: analgesics; muscle relaxants; antihistamines;decongestants; antacids; anti-inflammatories; antibiotics; antivirals;psychotherapeutic agents; insulin; nutraceuticals; nutritionalsupplements; and cardiovascular agents.

In yet another embodiment of the present invention a method ofdelivering a medicament is provided. The method comprising the steps of:providing a product including a coating that comprises at least 50% byweight of the product and surrounds a tableted compressible excipient.The coating includes a medicament; and chewing the product.

In a still further embodiment of the present invention a productcontaining a medicament or agent is provided. The product includes atableted compressible excipient center. The coating surrounds thetableted center and includes a medicament. The coating comprising atleast 50% by weight of the product. The coating includes taste maskingagents.

Moreover, in an embodiment of the present invention, a method ofmanufacturing a product containing a medicament or agent is provided.The method comprising the steps of: preparing a tableted compressibleexcipient center; and coating the tableted center with a powder and asyrup to create a coated product, at least one of the powder or syrupportion including a medicament or agent.

In an embodiment the powder and syrup are coated on the compressibleexcipient in alternating steps until a sufficient coating has been builtup.

In an embodiment the coating has a polished finish.

Accordingly, an advantage of the present invention is to provide newmethods for manufacturing products for delivering medicaments or agentsto an individual.

Furthermore, an advantage of the present invention is to provide animproved product containing a medicament.

Additionally, an advantage of the present invention is to provide amethod for administering medicaments that is more palatable than currentmethods.

Still further, an advantage of the present invention is to provide amethod of delivering medicaments to an individual that provides forincrease absorption and bioavailability as compared to medicaments thatare designed to be absorbed in the GI tract.

Further, an advantage of the present invention is to provide a method ofadministering a medicament or agent to an individual at a lower levelthan is typically administered orally while still achieving the sameeffect.

Furthermore, an advantage of the present invention is to provide amethod for administering medicaments or agents to an individual thatheretofore were administered parenterally.

Another advantage of the present invention is to provide a method formanufacturing products including medicaments or agents in the coating.

Moreover, an advantage of the present invention is to provide animproved method for drug delivery.

Further, an advantage of the present invention is to provide a chewableproduct that contains an agent that heretofore could not be provided ina chewable form that was palatable.

Still, an advantage of the present invention is to provide a method forensuring that a coated product that includes a medicament has a preciselevel of medicament.

An advantage of the present invention is that a coated product isprovided wherein the coating can absorb or lose moisture withoutapparent degradation.

Further, an advantage of the present invention is that a coated chewinggum product including medicament is provided having an extendedshelf-life.

Furthermore, an advantage of the present invention is that it canproduce medicament-containing products having precise sizes and shapes.

Another advantage of the present invention is to provide a method ofcontrolling the amount of agent containing coating that is used on acoated product.

Additional features and advantages of the present invention will bedescribed in and apparent from the detailed description of the presentlypreferred embodiments and the figures.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 illustrates generally an embodiment of the product of the presentinvention.

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS

The present invention provides improved methods for deliveringmedicaments and other agents to an individual as well as improvedproducts including such medicaments or agents and methods for producingsame.

Pursuant to the present invention, a medicament or agent is contained ina coating that surrounds a tableted compressible excipient center. Asused herein “tableted” means that a center is provided that has aprecise size (within an acceptable range) depending on the medicament oragent and shape. Thus allows an accurate control of the coating as wellas allows one to create products having specific sizes and shapes. In apreferred embodiment, the coating comprises at least 50% by weight ofthe entire product.

As the product is chewed, the medicament or agent is released into thesaliva. During continual chewing or crunching of the product between theteeth, the medicament or agent in the saliva is then forced through theoral mucosa in the buccal cavity due to the pressure created by thechewing. The oral mucosa has a thin epithelium and a rich vascularity.Thus, the oral mucosa favors drug absorption. In contrast to a typicallyorally ingested drug, wherein the solution is in contact too briefly forabsorption to be appreciable through the oral mucosa, it is believedthat during chewing, the agent and/or medicament remains in the buccalcavity and is forced through the oral mucosa. Also it has beensurprisingly found that an increase in the absorption of the drug isachieved as well as an increase in the bioavailability of the drug ascompared to typical oral administration. It has been found that the drugor agent is absorbed much quicker than if it was swallowed as in atypical oral administration. Indeed, the absorption approaches that of aparenteral administration, and bioavailability is also much greater thanoral administration.

Referring to FIG. 1, an embodiment of the product 10 of the presentinvention is illustrated. As illustrated, the product 10 includes atableted center 12. The tableted center can be any compressibleexcipient known in the art. Examples of such excipients includesaccharides such as dextrose and sucrose, and sugar alcohols such assorbitol and mannitol, and combinations of same.

Pursuant to the present invention, surrounding the tableted center 12 isa coating 14. The coating 14 includes a medicament or other activeagent.

As noted above, the tableted center 12 can be any size or shape,although in a preferred embodiment the center has a round shape.However, the key is that by tableting the center, one can control to aprecise relative standard deviation, the size of the center 12. Thisallows one to accurately control the amount of coating 14 that is placedaround the center 12 to create the resultant product. In this regard, ifthe center is too large or too small, the resultant coating will eitherbe greater or less than desired. Because the coating, as noted below,contains a medicament, if the size of the center 12 is not thepredetermined size, the level of medicament present in the resultantproduct could vary. By precisely controlling the size of the center,through the tableting process, one is ensured that a precise level ofcoating, and therefore medicament, can be provided and therebydelivered.

Additionally, by using the tableting process one can vary the size andshape of the resultant product. For example, for a product including ananalgesic, the product can have an aspirin shape. In a similar vein, forproprietary designs that are used for certain drugs, one can create thetableted center in the proprietary design allowing the resultant productto have the proprietary shape or design.

A variety of different tableting processes can be used. What isimportant is that a process is used that allows one to create a uniformcenter. For example, conventional drug tableting equipment orconfectionary tableting product equipment can be utilized. An example ofsuch equipment is the Stokes tableting machine available from StokesManufacturing Inc.

Referring now to the coating 14, preferably, the coating 14 comprisesapproximately 50% to about 75% by weight of the product. A variety ofcoatings can be utilized. For example, the coating can be a softamorphous coating. Or, the coating can be a recrystallized granularcoating. As discussed below, in a preferred embodiment, the coating isapplied as a syrup/powder composition.

Preferably, the coating 14 will include masking agents. In this regard,high-intensity sweeteners and appropriate flavors can be used to helpmask, along with the tableted center, any off notes that are present dueto the medicament or agent. It has been found that with respect tocertain medicaments or agents that may have an astringent or bittertaste that by adding a masking agent to the formulation, that a muchmore palatable formulation, including the medicament, can be provided.In this regard, even though the medicament in for example, its powderform may be bitter or have an offensive taste, the matrix used as thecoating of the present invention, including the masking agent, willhelp, along with the tableted center, to afford a product havingacceptable organoleptic properties. For example, it has beensurprisingly found that by solubilizing a powdered matrix of medicamentand masking agent, this increases the ability of the masking agent tocover up bitter and bad flavors produced by the medicament or agent. Byselecting specific masking agents in combination with the compressibleexcipients, based on the bad or off taste produced by the medicament,one can provide a palatable formulation.

For example, if one is attempting to cover an astringent flavor such asaspirin, one could use masking agents found to be effective againstastringency such as fructose and high-intensity sweeteners, e.g.saccharin, aspartame, sucralose, and acesulfame-k. In the case of amoderately bitter active ingredient, such as caffeine, one would useingredients such as glycine, ethyl maltol, zinc gluconate, licorice rootpowder, high-intensity sweeteners, etc. In the case of a very badtasking active ingredient such as acetaminophen it has been found thatpeppermint functions very well, but, may need to be augmented with ahigh-intensity sweetener, such as, for example, aspartame.

The masking agents, in an embodiment, are selected from the groupconsisting of: sucralose; zinc gluconate; ethyl maltol; glycine;acesulfame-k; aspartame; saccharin; fructose; xylitol; maltitol;isomalt; salt; spray dried licorice root; glycyrrhizin; dextrose; sodiumgluconate; sucrose; glucono delta-lactone; ethyl vanillin; and vanillin.

In an embodiment of the invention, sufficient masking agent and/ortableted excipient will be used to improve and provide acceptableorganoleptic properties to the product. As used herein to provide“acceptable organoleptic properties” means that the product will have asufficiently pleasant, or at least non-offensive taste, to allow theconsumer to chew the product allowing at least a portion of the productto dissolve in the mouth of the consumer. Whether a masking agent isnecessary and/or the amount of masking agent will vary depending onmedicament or agent and compressible excipient. Of course, if desired,more than one masking agent can be used, e.g., zinc gluconate and asweetener or flavor. In an embodiment, the masking agent may compriseapproximately 30% to about 99% by weight of the coating formulation.

In a preferred embodiment, the coating includes a high-intensitysweetener such as aspartame, sucralose, and acesulfame-k. Preferably,the high-intensity sweetener comprises approximately 0.1% to about 5% byweight of the coating. As noted above, the coating will include amedicament or agent. It is envisioned, that a variety of differentmedicaments and agents can be placed in the coating. For example, suchagents include, inter alia, stimulants such as caffeine and nicotine.Generally, such medicaments include, inter alia, analgesics,antibiotics, antivirals, antihistamines, anti-inflammatories,decongestants, antacids, muscle relaxants, psychotherapeutic agents,insulin, diuretics, vitamins, minerals, anesthetics, antitussives,anti-diabetic agents, bioengineered pharmaceuticals, nutraceuticals,nutritional supplements, and cardiovascular agents. It is envisioned,that depending on the medicament, the resultant product can be used totreat, inter alia: coughs; colds; motion sickness; allergies; fevers;pain; inflammation; sore throats; cold sores; sinus problems; diarrhea;diabetics; gastritis; depression; anxiety; hypertension; angina; andother maladies and symptoms. Specific agents/medicaments include, by wayof example and not limitation: caffeine; aspirin; acetaminophen;ibuprofen; ketoprofen; cimetodine; ranitidine; famotidine; dramamine;omeprazole; dyclonine; chlorpheniramine maleate; pseudoephedrine;hydrochloride; dextromethorphan hydrobromide; benzocanine; sodiumnaproxen; nicotine; hydroxycitric acid; chromium picolinate;phosphatidylserine; nicotine; insulin; echinacea purpurea; zinc; vitaminC; ginseng; kola nut; capsicum; nettle; passion flower; St. Johns Wort;valerian; Ma Huang/guarana; kava kava; and chamomile.

It is believed that the product of the present invention will allowchewable products to be provided that heretofore were not provided dueto offensive taste. Such products include, by way of example and notlimitation, excedrin, pseudoephedrin, and Ma Huang/guarana diet pills.

Preferably, the agents or medicaments are contained in the coating ofthe product at levels of approximately 50 micrograms to 500 milligrams.The specific levels will depend on the active ingredient. For example,if chromium picolinate is the active ingredient in an embodiment, itwould be present at a level of 50 micrograms per serving (3.0 grams ofcoated product); aspirin would be preset at a level of 325 milligramsper 3.0/gram serving. The level of medicament or agent in the coating ofthe product is selected so as to create, when the product is chewed, asufficiently high concentration of the medicament or agent in thesaliva.

For example, when the agent is a stimulant such as nicotine or caffeine,the level of the stimulant in the coating of the product should be suchthat it creates a saliva content of stimulant of approximately 15 to 440ppm after the product is chewed. At this level, a sufficient amount ofstimulant will be delivered to the chewer to create the effects setforth in the application. For a botanicals (e.g., chamomile, kava, kola,nut, ginseng, and Echinacea), the agent should be present in asufficient amount to create a saliva content of approximately 85 to 1100ppm after the product is chewed. For a metabolizer, for example,chromium picolineate and hydroxi-chitic acid, the agents should bepresent in an amount to create a saliva content of approximately 0.5 toabout 900 ppm after the product is chewed. If the agent is a vitamin ormineral (e.g., phosphatidy serine, vitamin C, and zinc), the agentshould be present in the amount to create a saliva content of thevitamin or mineral of approximately 10 to about 250 ppm after theproduct is chewed.

The level of medicament or agent in the coating is selected so as tocreate, when the product is chewed, a sufficiently high concentration ofthe medicament or agent in the saliva.

For example, when the agent is a stimulant such as caffeine, the levelof the stimulant in the compacted powder formulation should be such thatit creates a saliva content of stimulant of approximately 1% to about66% after the formulation is placed in the mouth. At this level, asufficient amount of stimulant will be delivered to the user to createthe effects set forth in the application. If a medicament is used suchas a medicinal (e.g., analgesics), sufficient medicinal should bepresent in the compacted powder formulation to create a salvia contentof approximately 1% to about 66%. For botanicals (e.g., chamomile, kava,kola, nut, ginseng, and Echinacea), the agent should be present in asufficient amount to create a saliva content of approximately 1% toabout 66%. For a metabolizer, for example, chromium picolineate andhydroxi-chitic acid, the agents should be present in an amount to createa saliva content of approximately 1% to about 66%. If the agent is avitamin or mineral (e.g., phosphatidy serine, vitamin C, and zinc), theagent should be present in the amount to create a saliva content of thevitamin or mineral of approximately 2% to about 30%.

Pursuant to the present invention, depending on the agent or medicament,the dosing regiment will change. For example, if the medicament is ananalgesic, the product would be taken on an as needed basis. Of course,similar to the oral administration of an analgesic, there would berestrictions on the doses taken, for example, not more often than oneproduct every four hours and not more often than four to five times aday.

If the agent is a stimulant, such as caffeine, to be used to enhanceperformance than the product would be ingested, in a preferredembodiment ten minutes or less before the performance.

A variety of methods can be used for constructing the coating of theproduct. Typically coatings are applied to products in a three-phaseoperation. In this regard, the first phase is to add a crude coating ofan alternate application of syrup and powder is applied. This isfollowed by a second phase called the finishing coating in which finerpowder and longer tumbling is used to produce a smooth finish. Finally ashellacking and polishing third phase is performed to provide ahigh-sheen smooth finish. In a preferred embodiment, the second phase isnot used and the third phase is optional. As noted above, in anembodiment, the products of the present invention can include 50% to 75%by weight coating. Using only the first phase of the method, this largepercent of coating can be applied to the product in a realistictime-frame.

In an embodiment, the coating comprises approximately 10 to about 30% byweight syrup and approximately 70% to about 90% by weight powder. Forexample, in a preferred embodiment, the coating comprises 20% syrup and80% powder.

In an embodiment of constructing the coated product, first the syrup isdistributed on the center. Then a portion of the powder is sprinkled ontop to dry up the syrup. A further amount of syrup is added and powdersupplied. This process is continued until the necessary amount of syrupand powder have been applied to the exterior of the center, e.g., 10 to20 coating layers or more are applied. The coating which can play animportant role as the masking agent, can include a combination of sugar,corn syrups, or in the case of a sugar-free product, variouscombinations of sugar alcohols, monomers, and polymers.

It has been found that by using this type of gross up coating processthat advantages are achieved for the product containing medicament ofthe present invention. This is true whether or not the medicament iscontained in the powder or in the syrup. Accordingly, if desired, themedicament can be contained in the syrup rather than in the powder.

Pursuant to the present invention, the coated product may not include ashellac or other finishing or shiny layer. It has been found, that thecoating can comprise merely a matte finish and still function, not onlysatisfactorily, but has some advantages. In this regard, typicallycoated products that retain moisture on the coating along with a shellaclayer may degrade due to moisture in the coating and therefore do nothave an extended shelf-life. This is especially true with the thickcoatings of the present invention. Such thick coatings absorb moremoisture than thinner coatings. If a matte finish is utilized, althoughthe thick coating layer can absorb the moisture, the matte finish allowsthe moisture to move into and out of the coating layer. This therebyprevents degradation of the product. Thus, the present inventionprovides a product having a thick coating with increased shelf-life.

The matte finish additionally not only allows a thick coating to be usedbut also ingredients that have high moisture absorption. Due to thematte finish, high moisture absorbing medicaments can be used withoutundue product degradation.

In an embodiment of the coating, dextrose or sucrose or combinationsthereof function as the main ingredient. In a preferred embodiment,dextrose is utilized and the dextrose comprises approximately 50 toabout 90% of the coating. The active ingredients or medicaments, in thecoating may comprise as much as 30% of the coating down to very smallamounts as long as the medication is efficacious. In a preferredembodiment, the flavors are powdered flavors and can range from 0.1% toapproximately 5%. High-intensity sweeteners such as aspartame,sucralose, and acesulfame-k can also be used in the coating and rangefrom approximately 0.1 to about 5% of the coating. As noted above, thesehigh-intensity sweeteners are excellent masking agents.

The coating including medicament or agent can surround a variety ofdifferent center compositions. In this regard, the center can be anycompressible excipient. For example, the center can be a compressiblesaccharide, e.g., dextrose, maltose, fructose, or sucrose, or acombination of same, or a compressible sugar alcohol, e.g., sorbitol,mannitol, and isomalitol or combinations of same.

If desired, additional excipients can be used with the above, such ashigh-intensity sweeteners and flavoring agents.

Preferred sweeteners include, but are not limited to, sucralose,aspartame, salts of acesulfame, altitame, saccharin and its salts,cyclamic acid and its salts, glycerrhizinate, dihydrochalcones,thaumatin, monellin, and the like, alone or in combination. In order toprovide longer lasting sweetness and flavor perception, it may bedesirable to encapsulate or otherwise control the release of at least aportion of the artificial sweetener. Such techniques as wet granulation,wax granulation, spray drying, spray chilling, fluid bed coating,coacervation, and fiber extension may be used to achieve the desiredrelease characteristics.

Flavoring agents may include essential oils, synthetic flavors ormixtures thereof including, but not limited to, oils derived from plantsand fruits such as citrus oils, fruit essences, peppermint oil,spearmint oil, other mint oils, clove oil, oil of wintergreen, anise andthe like. Artificial flavoring agents and components may also be used.Natural and artificial flavoring agents may be combined in anysensorially acceptable fashion.

Tableted Coated Product

The tableted gum will include a center and a coating. In an embodiment,the center will include the following ingredients in the followingranges:

Ingredient Percent Peppermint Flavor 0.44 Menthol Flavor 0.37 Dextrose97.49 Magnesium Stearate 1.70 100.00%

Ingredient Percent Dextrose 98.92 Sucrolose 0.19 Bubble Gum Flavor 0.19Magnesium Stearate 1.70 100.00%

Ingredient Grams Percent Menthol Flavor 30.00 1.88 Eucalyptus Flavor2.00 0.13 Aspartame 32.00 2.00 Magnesium Stearate 27.20 1.70 Dextrose1,508.80 94.30 1,600.00 100.00%

An embodiment of the coating for the product is as follows:

Ingredient Grams Acetaminophen 0.3490 Peppermint Flavor (dry) 0.0072Menthol Flavor (dry) 0.0062 Dextrose 1.4200 Sucrolose 0.0030 Aspartame0.0062 Glucose 0.2080 2.0000 g

Acetaminophen Coated Product

Center (1 gram) Ingredient Percent Peppermint Flavor 0.44 Menthol Flavor0.37 Dextrose 97.49 Magnesium Stearate 1.70 100.00%

Coating (1 gram) Ingredient Grams Acetaminophen 80.0 Encapsulated 20.0Aspartame Aspartame 50.0 Salt Flour 2.5 Dextrose 643.5 Flavor 4.0 800.0

Acetaminophen Coated Product

Center (1 gram) Ingredient % Peppermint Flavor 0.44 Menthol Flavor 0.37Dextrose 97.49 Magnesium Stearate 1.70 100.00%

Coating (2 grams) Ingredient Grams Acetaminophen 335.0 NaturalPeppermint 7.0 S.D. Menthol 6.0 Dextrose 1,221.0 Aspartame 32.0 1,601.0g

Pseudoephedrin Coated Product

Center (1 gram) Ingredient Grams Peppermint Flavor 0.44 Menthol Flavor0.37 Dextrose 97.49 Magnesium Stearate 1.70 100.00%

Coating (2 grams) Ingredient Grams Dextrose 1,476.00 Eucalyptus* 2.00Menthol* 30.00 Aspartame 32.00 Pseudoephedrin 60.00 1,600.00 *sprayeddried

Peppermint Caffeine Coated Product

Gum Center (1 gram) Ingredient Grams Peppermint Flavor 0.44 MentholFlavor 0.37 Dextrose 97.49 Magnesium Stearate 1.70 100.00%

Coating (2 grams) Ingredient Grams Caffeine 100.0 Peppermint 13.0Dextrose 1,455.0 Aspartame 32.0 1,600.0

By way of example, and not limitation, examples demonstrating thebenefits of placing a medicament in a coating surrounding a chewableconfectionary, chewing gum, will now be provided.

Experiment No. 1

The following gum center formulation was made as a gum pellet center:

Gum Center % Gum Base 47.00 Sorbitol 39.52 Liquid Sorbitol 7.50 Flavors2.36 Encapsulated Flavors 2.00 Glycerin 0.75 Encapsulated Sweeteners0.87 100.00

The gum pellet was coated with the following gum coating formulation:

Gum Coating % of Syrup 1 % of Syrup 2 Xylitol 63.03 74.35 Water 11.1413.15 40% Gum Tahla Solution 20.87 7.96 Titanium Dioxide Whitener 0.370.44 Peppermint Flavor¹ 0.81 0.00 Caffeine 3.78 4.10 100.00 100.00¹Flavor added in 2 additions after 10th and 15th within coating syrup 1.

Initial center piece weight was 0.956 grams. Gum was coated to afinished piece weight of 1.46 grams to give a 34.5% coating. Coatingsyrup 1 was used to coat the first 60% of the coating to a piece weightof 1.26 grams. Coating syrup 2 was used to coat to the final pieceweight. Individual piece analysis of 5 pieces yielded a level of 26.1 mgof caffeine per piece. For a 2 piece dosage, caffeine level is 52.2 mg.

This gum product was used in a caffeine absorption study to comparerelease and absorption uptake of caffeine from gum and beverages. Thetest results showed that gum is a faster delivery vehicle for caffeinewhen compared to the same level in beverages as measured by blood plasmacaffeine. Caffeine was taken up faster in the test subject's plasmaafter delivery via gum than after delivery of same caffeine dose viacoffee, cola, and tea.

Comparisons of caffeine delivery between chewing gum and the threebeverages are demonstrated by statistically significant differences inone or more of the following parameters:

1. Plasma caffeine concentration is significantly greater for gum vs.beverages within the first 10 to 30 minutes after caffeine delivery.This correlates to faster uptake.

2. Plasma absorption rate constant (A-rate) larger for gum vs. one ormore beverages (2). Plasma absorption half life (abs. half-life) smallerfor gum vs. one or more beverages (2). Time of peak caffeine plasma.

A clinical trial study was performed where six subjects participated inthe test, blood was drawn and plasma separated. Blood sampling occurredprior to, and at present time intervals following a caffeine level of50-55 mg released through the test delivery vehicle. Five differentstudies were completed: gum (with saliva swallowed, G2), gum (withsaliva expectorated, G3), coffee (ingested COF), cola (ingested COK),and tea (ingested T). Blood samples of 5 ml were collected and theplasma portion separated, stored, and extracted and analyzed. A methodwas developed for the extraction and analysis of caffeine in fluids,which reports results as the concentration of caffeine in the plasma.

Data from the six subjects participating in the study were compiled,analyzed, and graphed, with mean plasma caffeine concentrations atspecific time intervals determined. Analysis of variance (ANOVA) wereperformed on the means to determine statistical significance.

Phamacokinetic parameters were determined through Wagner's 1967 Methodof Residuals using a pharmacokinetic software package. Absorption rateconstants and absorption half-life were also determined through theanalysis of the absorption phase of the plots by linear regression sincethe absorption phase followed zero order kinetics.

The conclusions were as follows:

1. There was a faster uptake of caffeine in plasma during the early timeintervals post dose 10 minutes to 25 minutes (T10-T25) via gum deliveryvs. the same level of caffeine delivered via coffee and cola. Forexample, the average level of plasma caffeine (at T=10 minutes) presentafter gum chew is 0.545 μg/ml compared to 0.186 μg/ml for coffee and0.236 μg/ml for cola. In other words, with the same level of caffeinebeing delivered from the three different vehicles, at T10 there is 3times more caffeine present in plasma after chewing gum than fromingesting coffee and 2 times more caffeine from gum than from cola. Theresults of the tea study proved to be too variable due to instrumentproblems and repeat freeze/thawing of the samples. They were notincluded in the calculations.

2. Classical pharmacokinetic parameters, T-max, A-rate constant, abs.half-life, do not tell the story of faster uptake in the time intervalof interest (T10-T25) in this study. This is due in part to thecalculation using the Method of Residuals. This method was derived usingclassical pharmacokinetic curves which do not have much fluctuation inthe data in that the drug concentration (usually measured every hour)increases to a sharp T-max, then decreases, without any fluctuation. Incomparison, the data did contain minor fluctuations, due most likely toa combination of factors: measurement of plasma concentrations everyfive minutes rather than every quarter hour to one hours, caffeinebinding with plasma protein, combination of both sublingual and gutabsorption being detected. The plasma caffeine concentration followedthe same trends as in classical pharmacokinetic curves, except that theconcentration increased to a broad T-max, then decreased, and some ofthe points in the curve fluctuated up and down.

A-rate constant and abs. half-life determinations were also made throughlinear regression. No significant differences were noted in the means,though a trend was noted: the A-rate for the gum study (G2) was greaterthan that for coffee and cola for subjects 1-4 and the abs. half-lifefor the G2 study was less than that for coffee and cola for subjects1-4. For example, the G2 abs. half-life averaged 13±4 minutes forsubjects 1-4, 28±2 minutes for subjects 5 and 6, indicating fasterabsorption between the subjects. The amount of caffeine absorbedsublingually was 21±7 mg for subjects 1-4, and 10±1 mg for subjects 5and 6 accounting for the increased A-rate and decreased abs. half-lifein subjects 1-4. An ANOVA separating subjects 1-4 from 5 and 6 indicatedthat for subjects 1-4 cola abs. half-life is statistically greater thanG2 abs. half-life (p=0.10), and the G2 A-rate is statistically greaterthan both the cola and coffee A-rate (p=0.05).

3. It was shown that significant levels of caffeine are absorbedsublingually directly into the bloodstream via delivery from gum. Thiswas demonstrated through the testing of caffeinated gum where the salivawas expectorated. Even though the saliva was expectorated, 20-50% of thecaffeine was absorbed through the oral cavity. This accounts for theearly uptake into the bloodstream.

Experiment No. 2

The following formulation was made:

Gum Center % Gum Base 33.00 Calcium Carbonate 13.00 Sorbitol 44.23Glycerin 4.00 Flavors 2.32 Encapsulated Caffeine² 1.50 Free Caffeine0.45 Lecithin 0.60 Encapsulated Sweeteners 0.90 100.00 Gum CoatingCoating Syrup 3.0% Coating Syrup 4.0% Xylitol 64.14 76.23 Water 11.1413.15 40% Gum Tahla Solution 20.87 7.96 Titanium Dioxide Whitener 0.400.40 Peppermint Flavor³ 1.40 0.00 Sweeteners 0.27 0.27 Carnauba Wax/0.00 0.27⁴ Talc Polishing Agents Caffeine 1.78 1.72 100.00 100.00 ²Spraydried maltodextrin/caffeine at 50% active caffeine. ³Flavor added in 3additions after 3 separate syrup addition within coating syrup 1.⁴Polished after completion of coating.

Initial center piece weight was 0.995 grams. Gum was coated to afinished piece weight of 1.52 grams to give a 34.5% coating. Coatingsyrup 3 was used to coat the first 60% of the coating to a piece weightof 1.30 grams. Coating syrup 4 was used to coat to the final pieceweight. Individual piece analysis of 5 pieces yielded a level of20.0±0.8 mg of caffeine per piece. For a two piece dosage, caffeinelevel is 40.0 mg.

This gum product was used in a caffeine absorption study to comparerelease and absorption uptake of caffeine from gum versus pills. Thetest results showed that gum is a faster delivery vehicle for caffeinewhen compared to a similar level in a pill as measured by blood plasmacaffeine. Caffeine was taken up faster in the test subject's plasmaafter delivery via gum than after delivery of same caffeine dose via apill.

Data from the six subjects participating in each study were compiled,analyzed, and graphed, with mean plasma caffeine concentrations atspecific time intervals determined. Analysis of variance (ANOVA) andStudent t-Tests were performed on the means to determine statisticalsignificance. Pharmacokinetic parameters were done using apharmacokinetic software package. The gums tested were pellet fromExperiment No. 5, containing all the caffeine in the coating anddelivering approximately 50 mg caffeine after chewing two pellets(designated as G2, G4, or 50 mg pellet), and Experiment No. 6,containing caffeine in the coating and center, and deliveringapproximately 40 mg caffeine after chewing two pellets (designated G5 or40 mg pellet). Both pellets were compared to Pro-Plus™ 50 mg tablet ismanufactured by the product license holder: PP Products, 40 BroadwaterRoad, Welayn Garden City, Harts, AL7 Bay, UK. Caffeine analysis wereanalyzed at 48.3 mg±1.4 mg caffeine per pill (avg. of n=5).

It was concluded that caffeine uptake in the bloodstream was faster forgum than a pill, based on the following:

1. Faster uptake of plasma caffeine via gum delivery was found duringthe early time intervals post dose 5 minutes to 50 minutes (T5-T50) whencompared to the same level of caffeine delivered via a pill (50 mg). Forexample, with the same level of caffeine being delivered from the twodifferent vehicles, on average, at T5 there is 30 times more caffeinedetected in plasma after chewing gum (0.205 μg/ml). Average plasmacaffeine levels significantly greater than the pill at a=0.01 for T5,and a=0.005 for T10.

2. Classical pharmacokinetic parameters, T-Max (time for peak plasmacaffeine concentration) and Abs. half-life (absorbence half-life, timefor caffeine concentration to be half of peak) were significantlydifferent for caffeine delivered via 50 mg pellet gum (Experiment No. 5)than via a 50 mg pill. Faster uptake of plasma caffeine was demonstratedvia delivery from gum compared to a pill due to the average plasma Abs.half-life and average plasma T-Max being significantly smaller for gumthan the pill. For the 50 mg pellet gum, the average Abs.half-life=12.84 min. and the average T-Max=36.5 min. compared to the 50mg pill with an average Abs. half-life=24.47 min (pill significantlygreater than gum, a=0.0075), and an average T-Max=73.67 min (pillsignificantly greater than gum, a=0.0075), and an average T-Max=73.67min (pill significantly greater than gum, a=0.005). In other words,after ingesting a pill, it takes a longer amount of time to reach halfof the peak plasma caffeine concentration and the peak plasma caffeineconcentration than after chewing gum delivering the same level ofcaffeine.

3. The Abs. Rate Const. (absorption rate constant, rate at whichcaffeine absorbs into the bloodstream) was significantly greater for 50mg pellet gum (Experiment No. 5) than for the 50 mg pill, indicatingthat caffeine is absorbed at a greater rate after gum delivery thanafter delivery of the same dosage via a pill. For the 50 mg pellet gum,the average Abs. Rate Const.=0.060 compared to the 50 mg pill with anaverage Abs. Rate const.=0.031 (gum significantly greater than pill,a=0.005).

4. The test also demonstrated faster uptake of plasma caffeine via theproduct of Experiment No. 6, 40 mg pellet gum, delivery during the earlytime intervals post dose 10 minutes to 30 minutes (T10-T30) whencompared to 50 mg of caffeine delivered via a pill. Significance levelsranged from a=0.05 to a=0.20. For example, the average level of plasmacaffeine (at T=10 minutes) present after 40 mg pellet gum is chewed is0.228 μg/ml compared to 0.034 μg/ml for pill (difference was slightlysignificant, a=0.2). In other words, with caffeine being delivered fromthe two different vehicles at T10 there is 6.7 times more caffeinedetected in plasma after chewing the product of Experiment No. 6 gumcaffeine than after ingesting a pill, even though the pill deliveredapproximately 50 mg caffeine, and the product of Experiment No. 6delivered approximately 40 mg. At T5, on average there was 13 times morecaffeine detected in plasma after chewing Experiment No. 6 gum thanafter ingesting a pill.

5. Classical pharmacokinetic parameters, T-Max and Abs. half-life weresignificantly different for caffeine delivered via the product ofExperiment No. 6 40 mg pellet gum than via a 50 mg pill. Faster uptakeof plasma caffeine was demonstrated via delivery from the product ofExperiment No. 6 gum compared to a pill due to the average plasma Abs.half-life and average plasma T-Max being significantly smaller for gumthan the pill. For the 50 mg Experiment No. 5 gum, the average Abs.half-life=18.33 min. and the average T-Max=45 min compared to the 50 mgpill with an average Abs. half-life=24.47 min (pill significantlygreater than gum, a=0.05), and an average T-Max=73.67 min (pillsignificantly greater than gum, a=0.15). Even though the product ofExperiment No. 6 delivered 40 mg caffeine compared to delivery of 50 mgvia a pill, it still took a longer amount of time to reach half of thepeak plasma caffeine concentration for the pill than for the gum.

6. It was concluded that gums formulated with all the caffeine in thepellet coating delivered caffeine more quickly to the plasma than gumsformulated with the caffeine split between the coating and the centerbased upon the following:

Classical pharmacokinetic parameters T-Max and Abs. half-life weregreater than pill for both 50 mg pellet and Experiment No. 5 though thelevel of significant different was much greater for the 50 mg pellet(Experiment No. 5) (a=0.0075 and a=0.005 respectively) than the productof Experiment No. 6 (a=0.05, a=0.15). The Abs. Rate Const. wassignificantly lower for the pill than for either the 50 mg pellet or thethe product of Experiment No. 6. Again, the level of significantdifference was greater for the 50 mg pellet (Experiment No. 5), a=0.005compared to 0.20 for the product of Experiment No. 6.

7. Combining the conclusions from the two completed caffeine studies, itappears that rate of caffeine uptake in plasma via the various deliveryvehicles tested follow this pattern:

Pellet with caffeine all in coating>Pellet with caffeine split betweencoating and center=Beverages coffee/cola>Pill

Caffeine was chosen as a model for drug delivery tests because it is afood approved, pharmacologically active agent that is readily detectedin plasma at a wide range of dosage levels. It is widely consumed via anumber of delivery vehicles, including liquids (coffee, cola, andpills). Drugs are administered through different delivery vehicles, twooral delivery vehicles being liquid syrups and pills. Testingcaffeinated beverages and pills vs. caffeinated gums should give anindication of how similar drugs administered as liquids or coated pillsvs. coated gums could behave.

It should be understood that various changes and modifications to thepresently preferred embodiments described herein will be apparent tothose skilled in the art. Such changes and modifications can be madewithout departing from the spirit and scope of the present invention andwithout diminishing its intended advantages. It is therefore intendedthat such changes and modifications be covered by the appended claims.

1. A product comprising a medicament comprising: a compressed centercomprising at least one compressible saccharide or sugar alcohol; and acoating comprising a medicament that surrounds the compressed center,the coating comprising at least 50% by weight of the product.
 2. Theproduct of claim 1, wherein the medicament is selected from the groupconsisting of analgesics, muscle relaxants, antibiotics, antivirals,stimulants, antihistamines, decongestants, anti-inflammatories,antacids, psychotherapeutic agents, insulin, vitamins, minerals,nutraceuticals, nutritional supplements, cardiovascular agents, andcombinations thereof.
 3. The product of claim 1, wherein the coatingincludes a taste masking agent.
 4. The product of claim 3, wherein thetaste masking agent is selected from the group consisting of zincgluconate, ethyl maltol, glycine, acesulfame-k, aspartame, saccharin,fructose, xylitol, isomalt, maltitol, spray dried licorice root,glycerrhizine, sodium gluconate, glucono delta-lactone, ethyl vanillin,dextrose, sucralose, vanillin, ethyl maltol, and combinations thereof.5. The product of claim 3, wherein the taste masking agent comprisesapproximately 30% to about 99% by weight of the coating.
 6. The productof claim 1, wherein the coating includes approximately 0.1% to about 5%by weight of a high-intensity sweetener selected from the groupconsisting of aspartame, sucralose, saccharine, acesulfame-k, andcombinations thereof.
 7. The product of claim 1, wherein the compressedcenter includes dextrose.
 8. The product of claim 1, wherein the coatingdoes not have a shellac layer.
 9. A product comprising a medicamentcomprising: a compressed center comprising at least one saccharide orsugar alcohol; and a coating comprising a medicament that surrounds thecenter, the coating comprising at least 50% by weight of the product.10. The product of claim 9, wherein the medicament is selected from thegroup consisting of analgesics, muscle relaxants, antibiotics,antivirals, stimulants, antihistamines, decongestants,anti-inflammatories, antacids, psychotherapeutic agents, insulin,vitamins, minerals, nutraceuticals, nutritional supplements,cardiovascular agents, and combinations thereof.
 11. The product ofclaim 9, wherein the coating comprising a taste masking agent.
 12. Theproduct of claim 11, wherein the taste masking agent is selected fromthe group consisting of zinc gluconate, ethyl maltol, glycine,acesulfame-k, aspartame, saccharin, fructose, xylitol, isomalt,maltitol, spray dried licorice root, glycerrhizine, sodium gluconate,glucono delta-lactone, ethyl vanillin, dextrose, sucralose, vanillin,ethyl maltol, and combinations thereof.
 13. The product of claim 11,wherein the taste masking agent comprises approximately 30% to about 99%by weight of the coating.
 14. The product of claim 9, wherein thecoating comprising approximately 0.1% to about 5% by weight of ahigh-intensity sweetener selected from the group consisting ofaspartame, sucralose, saccharine, acesulfame-k, and combinationsthereof.
 15. The product of claim 9, wherein the center includesdextrose.
 16. The product of claim 9, wherein the coating does not havea shellac layer.
 17. A product including a medicament that hasacceptable organoleptic properties comprising: a compressed center thatis defined by at least one excipient; and a coating that at leastsubstantially surrounds the center and comprising a medicament, thecoating comprising at least 50% of the product by weight.
 18. Theproduct of claim 17, wherein the medicament is selected from the groupconsisting of analgesics, muscle relaxants, antibiotics, antivirals,stimulants, antihistamines, decongestants, anti-inflammatories,antacids, psychotherapeutic agents, insulin, vitamins, minerals,nutraceuticals, nutritional supplements, cardiovascular agents, andcombinations thereof.
 19. The product of claim 17, wherein the excipientis selected from the group consisting of saccharides, sugar alcohols,and combinations thereof.
 20. The product of claim 17, wherein a tastemasking agent comprises approximately 30% to about 99% by weight of thecoating.
 21. The product of claim 17, wherein the coating compromisesapproximately 0.1% to about 5% by weight of a high-intensity sweetenerselected from the group consisting of aspartame, sucralose, saccharine,acesulfame-k, and combinations thereof.